This invention relates generally to a method for treating conditions responsive to nicotine therapy. More specifically, the invention relates to pulmonary administration of nicotine to effect smoking cessation.
Diseases related to cigarette smoking, such as lung disease, heart disease and cancer, claim an estimated 400,000 lives each year. The combustion of tobacco produces poisons and carcinogens that present a significant health hazard for smokers and non-smokers alike. Nicotine is a principal component of tobacco, and the most pharmacologically active. It is physically addictive, making it extremely difficult for a smoker to quit.
Smoking a cigarette delivers nicotine vapors to the lungs, where nicotine is rapidly absorbed through the arteries and delivered to the brain. Nicotine interacts with nicotinic cholinergic receptors in the brain to induce the release of neurotransmitters and produce an immediate rewardxe2x80x94the xe2x80x9crushxe2x80x9d that smokers experiencexe2x80x94that is associated with a rapid rise in blood level. A persistent stimulus is also produced, and is associated with a high blood level of nicotine. As such, the dopaminergic reward system is activated which eventually results in nicotine dependency. Complex behavioral and social aspects of smoking, e.g., the hand-to-mouth ritual, etc., are also habit-forming.
A therapeutic approach to aid in smoking cessation is to provide the smoker with nicotine from sources other than cigarettes. Nicotine can be administered orally. However, after oral administration it is absorbed from the gut into the portal blood and degraded promptly by the liver. Nicotine can also be administered parenterally, e.g., intravenously, transcutaneously, muscosally, etc. Although preparations of nicotine appropriate for intravenous administration have been available for some time, intravenous cannulation as a means for gaining access to the circulation for the administration of nicotine on demand is not a socially acceptable alternative to cigarette smoking. There are also a number of commercially available nicotine replacement therapies that deliver nicotine to the systemic circulation via absorption through mucosal membranes or the skin. These include nicotine-containing chewing gum, sachets, transdermal patches, capsules, tablets, lozenges, nasal sprays and oral inhalation devices.
In particular, nicotine delivery via inhalation offers the benefit of addressing the psychological component of cigarette smoking in addition to the physiological dependence on nicotine. Nicotine inhalation systems release nicotine as a vapor (see U.S. Pat. Nos. 5,167,242; 5,400,808; 5,501,236; 4,800,903; 4,284,089; 4,917,120; 4,793,366), aerosol (see U.S. Pat. Nos. 5,894,841; 5,834,011) or dry powder (see U.S. Pat. No. 5,746,227) when air is inhaled through the inhaler. A droplet ejection device (U.S. Pat. No. 5,894,841) has also been described that delivers a controlled dose of nicotine via inhalation. These systems deliver low doses of nicotine to the mouth and throat, where nicotine is absorbed through the mucosal membranes into the circulation. Some inhalation therapies feature devices that simulate or approximate the look, feel and taste of cigarettes.
Currently available nicotine replacement therapies, such as transdermal and buccal systems where absorption occurs slowly, provide a low, steady-state blood level of nicotine to the patient without the early nicotine concentration spike that occurs due to immediate, arterial delivery of nicotine to the brain. Thus, the goal of these therapies is to eliminate the immediate, pleasurable effects associated with smoking while still alleviating the nicotine withdrawal effects until complete cessation of nicotine is physically and psychologically possible for the patient. The perceived advantage of these therapies is that the likelihood of abusing the nicotine delivery device (e.g., transdermal patch, nicotine chewing gum, nicotine inhalers, etc.) is very low. However, it is believed by some that it is because of this complete lack of xe2x80x9crushxe2x80x9d experienced by the patient, that the success rates of these conventional therapies are not higher than they are.
Thus, the need remains for a smoking cessation therapy that delivers a precise dose of nicotine directly to the lungs and, therefore, directly into the arterial circulation in a profile that mimics the blood levels achieved by cigarette smokingxe2x80x94providing an initial sharp rise in blood level followed by a slow release of nicotinexe2x80x94making it possible for the user to be weaned off of nicotine and to quit smoking.
A system for aiding a patient in quitting smoking is disclosed. The system is comprised of a means for the delivery of aerosolized nicotine which makes it possible to gradually decrease the amount of nicotine that the patient receives. The system comprises a means for aerosolizing a formulation comprised of nicotine and a means for decreasing the amount of nicotine formulation which is aerosolized and/or the amount which actually reaches the patient""s circulatory system. The amount of nicotine aerosolized or effectively delivered to the patient can be changed in several different ways using either the device aerosolization mechanism, the formulation or formulation containers loaded into the device.
A preferred system of the invention aerosolizes the liquid formulation by applying force to a container of nicotine formulation and causing the nicotine formulation to be moved through a porous membrane which results in creating particles of nicotine formulation which are inhaled by the patient. This system modifies the amount of nicotine aerosolized by providing a plurality of different containers or different groups of containers wherein the different containers or groups of containers contain different concentrations of nicotine. A patient using the system can utilize packets of nicotine formulation containing a high concentration initially and then gradually switch towards lower and lower concentrations so that the patient receives essentially the same amount of aerosolized formulation but receives gradually reduced amounts of nicotine due to the reduced concentration of the nicotine in the formulation.
The same procedure described above can also be carried with a dry powder inhaler (DPI). Using the dry powder inhaler technology the packets of dry powder nicotine formulation loaded into the device can initially contain a relatively high concentration of nicotine. Thereafter, the concentration of nicotine in the dry powder formulation added into the device is gradually decreased. Thus, using this system the same amount of dry powder is aerosolized, but the amount of nicotine is gradually decreased by decreasing the concentration or simply the total amount of nicotine in the dry powder package loaded into the device.
Additionally, the same procedure can be utilized with a conventional metered dose inhaler (MDD device. It is somewhat more difficult to utilize the invention with an MDI device. However, small pressurized canisters conventionally used with MDIs can contain different concentrations of nicotine along with the propellant. By using a first container which includes the highest concentration of nicotine and gradually changing to lower and lower concentrations of nicotine in the pressurized canister the desired result of reducing the amount of nicotine delivered to the patient can be obtained. The same results could be obtained by gradually decreasing the amount of formulation released when the value of a container is opened.
When using a dry powder inhaler or a system which aerosolizes a liquid formulation by moving the formulation through a porous membrane, it is possible to decrease the amount of nicotine gradually by making changes in the device, or more specifically the operation of the device. For example, a dry powder inhaler often utilizes a burst of air in order to aerosolize the dry powder. The burst of air could be decreased so that not all of the powder is fully aerosolized or so that the powder is not aerosolized in a completely efficient manner. In a more preferred embodiment the system for aerosolizing liquid formulation is adjusted at different points so that different amount of pressure are applied to the formulation making it possible to aerosolize decreasing amounts of formulation and allowing the patient to be gradually weaned off of nicotine.
The most preferred embodiment of the invention involves the use of a system which aerosolizes liquid formulations of nicotine contained within individual packets which packets include a porous membrane. As indicated above the amount of nicotine that can be changed by changing the amount of or concentration of nicotine in the packets. However, it is also possible to decrease the amount of nicotine actually delivered to the patient""s circulatory system by changing the size of the pores in the membrane. When the pore size is in a preferred range then a relatively high concentration of the formulation aerosolized will reach the patient""s lungs and move from the lungs into the patient""s circulatory system. However, by making the pores larger the aerosolized particles created also become larger. The larger particles will not move into the lungs as efficiently as the smaller particles. Further, the larger particles may be deposited in areas where they are not readily absorbed into the patient""s circulatory system.
Thus, in accordance with a preferred embodiment of the invention, a plurality of different containers are produced. The containers are different from each other in that they contain different amounts or concentrations of nicotine. Alternatively, the containers are different from each other in that they have different porous membranes on them which make it possible to aerosolize the formulation in a somewhat less efficient manner over time. It is possible to combine both or all three features together. More specifically, it is possible to produce containers which contain (1) smaller concentrations of nicotine; (2) smaller amounts of nicotine; or (3) have porous membranes which have different size or amounts of pores so as to less efficiently aerosolize the formulation present in the container.
A method for aiding in smoking cessation and for treating conditions responsive to nicotine therapy by the administration of nicotine is disclosed. A formulation comprised of nicotine is aerosolized. The aerosol is inhaled into the lungs of the patient. Once inhaled, particles of nicotine deposit on lung tissue and, from there, enter the patient""s circulatory system. Because delivery is to the lungs, rather than to the oral mucosa or through the skin, the nicotine is immediately delivered, along with freshly oxygenated blood, to the heart via the pulmonary arteries where it is then pumped via the aorta to the arterial circulatory system, which is responsible for the delivery of oxygenated blood to the patient""s entire body. The carotid arteries, in particular, transport the nicotine-containing oxygenated blood directly to the brain where it is then perfused throughout the brain by the neurovasculature system. Thus, the patient""s serum nicotine level in the brain is quickly raised to a desired levelxe2x80x94as quickly as if the user were smoking, providing the xe2x80x9crushxe2x80x9d effect. The smoker isn""t immediately deprived of the psychological pleasures of smoking and, as such, is more likely to successfully complete the smoking-cessation treatment. Because the methods of the invention substantially bypass the body""s processes that would effectively metabolize (e.g., by the liver) or dilute (e.g., by systemic distribution via the venous circulatory system) the nicotine dose and thus minimize the effect of the nicotine dose prior to delivery to the brain, the inventive methodologies are able to produce arterial plasma concentrations of nicotine similar to those experienced during cigarette smoking.
Subsequently, the patient""s dependence on nicotine is reduced by gradually reducing the dose of nicotine. The dose of nicotine is reduced by progressively increasing the size distribution of the aerosolized nicotine particles delivered to the patient. This decreases the amount of nicotine delivered to the patient""s lungs, with the result that nicotine absorption is less immediate and the nicotine blood plasma level is lower.
A method of treatment is disclosed, comprising:
(a) aerosolizing a formulation comprised of nicotine creating aerosolized particles which are sufficiently small as to enter the alveolar ducts;
(b) allowing a patient to inhale the aerosolized particles of (a) thereby causing nicotine to enter the patient""s blood at air/blood diffusion membranes;
(c) repeating (a) and (b) a plurality of times;
(d) aerosolizing a formulation comprised of nicotine creating aerosolized particles which are too large to enter alveolar ducts but sufficiently small to enter primary and secondary bronchioles;
(e) allowing the patient to inhale the aerosolized particles of (d) into primary and secondary bronchioles; and
(f) repeating (d) and (e) a plurality of times.
The method is preferably further comprised of:
(g) aerosolizing a formulation comprised of nicotine creating aerosolized particles which are too large to enter primary and secondary bronchioles but sufficiently small to enter the small bronchi;
(h) allowing the patient to inhale the aerosolized particles of (g) into small bronchi; and
(i) repeating (g) and (h) a plurality of times.
Another method of treatment is disclosed which includes the steps of:
(a) aerosolizing a pharmaceutical formulation comprised of nicotine to create aerosolized particles having a size in the range from about 0.5 to 12 ∥; and
(b) allowing the patient to inhale the aerosolized particles of (a) thereby causing nicotine to directly enter the patient""s arterial system from the patient""s lungs.
The method may further include the step of:
(c) repeating steps (a) and (b) a plurality of times.
In certain embodiments, this method may further include the steps of:
(d) performing step (c) over a first period of time wherein the nicotine is present in a first concentration; and
(e) performing step (c) over a second period of time wherein the nicotine is present in a second concentration which is less than the first concentration.
In other embodiments, this method may further include the steps of:
(d) performing step (c) over a first period of time wherein the aerosolized particles have a first size; and
(e) performing step (c) over a second period of time wherein the aerosolized particles have a second size which is greater than the first size.
An aspect of the invention is a method of treatment whereby nicotine or a nicotine substitute is aerosolized, inhaled into areas of the respiratory tract including the lungs and provided to the arterial circulatory system of the patient at levels sufficient to simulate cigarette smoking.
An advantage of the invention is that the nicotine levels are raised almost immediately on administration.
Another advantage of the invention is that the patient can gradually be weaned off of the immediate effect of nicotine obtained via smoking and gradually weaned off of the need of nicotine by, respectively, increasing particle size and decreasing dose size or concentration.
A feature of the invention is that aerosolized particles of nicotine having a diameter of about 0.5 to 8 microns (xcexc) are created and inhaled deeply into the lungs, thereby enhancing the speed and efficiency of administration.
It is an object of this invention to describe the utility of delivering nicotine by inhalation as a means of treating conditions responsive to nicotine therapy, and particularly for smoking cessation therapy.
It is another object of this invention to describe the utility of varying the distribution of aerosolized particles of nicotine inhaled as a means of treating smokers wishing to quit.
It is another object of this invention to describe liquid formulations (which includes suspensions) of nicotine and derivatives thereof appropriate for pulmonary delivery.
It is another object of this invention to describe how nicotine delivered via the lung can quickly increase arterial nicotine blood plasma concentration levels.
An aspect of the invention is a method whereby larger and larger particles of aerosolized nicotine are administered to a patient over time in order to first wean a smoking patient off of the addiction to the immediate effects of nicotine and, thereafter, reduce the amount of nicotine in order to wean the patient completely off of the addiction to nicotine, thereby allowing the patient to quit smoking.
A feature of this invention is that it allows for the formation of nicotine particles in different sizes designed for delivery to different areas of a patient""s lungs.
An advantage of the invention is that it allows the patient to be weaned off of (1) the need for immediate nicotine delivery as obtained when smoking, and (2) the need for nicotine at all.
These and other aspects, objects, advantages, and features of the invention will become apparent to those skilled in the art upon reading this disclosure.